Med Clin N Am 91 (2007) 805–843

Recent Advances in Basic and ClinicalNanomedicine

K. John Morrow, Jr, PhDa, Raj Bawa, MS, PhDb,c,d,*,Chiming Wei, MD, PhD, FACC, FAHA, FAANe

aNewport Biotechnology Consultants, 625 Washington Avenue, Newport, KY 41071, USAbBawa Biotechnology Consulting, LLC, 21005 Starflower Way, Ashburn, VA 20147, USA

cRensselaer Polytechnic Institute, 110 8th Street, J Building, Troy, NY 12180, USAdExtended Learning InstitutedNorthern Virginia Community College,

Annandale, VA 22003, USAeDepartment of Surgery, Johns Hopkins University School of Medicine,

600 N. Wolfe Street/Harvey 606, Baltimore, MD 21205, USA

History of nanotechnology

Most accounts of the history and origins of nanotechnology begin withRichard Feynman’s historic 1959 lecture at the California Institute of Tech-nology titled ‘‘There is Plenty of Room at the Bottom,’’ in which he out-lined the idea of building objects from the bottom up (ie, from individualatoms) [1]. This brilliant suggestion did not gain much traction until themid-1980s, when Eric Drexler published Engines of Creation in 1986, a pop-ular treatment of the promises and potentials of nanotechnology [2]. Drex-ler envisioned a molecular nanotechnology discipline that would allowmanufacturers to fabricate products from the bottom up with precise mo-lecular control. This technology would allow every molecule to be insertedin its specific place, so that the manufacturing processes would be clean,efficient, and highly productive. The belief was that these design and assem-bly systems would maintain much higher throughputs than modernmanufacturing techniques that use macroscale manipulators to fabricatedevices. Although Feynman’s vision has resulted in several nanoassemblyprocesses, we foresee that large-scale, full-blown molecular nanotechnologyis likely to be decades away.

* Corresponding author. Bawa Biotechnology Consulting, LLC, 21005 Starflower Way,

Ashburn, VA 20147.

E-mail address: bawabio@aol.com (R. Bawa).

0025-7125/07/$ - see front matter � 2007 Elsevier Inc. All rights reserved.

doi:10.1016/j.mcna.2007.05.009 medical.theclinics.com

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Nanotechnology is hard to define

One of the problems facing nanotechnology is the confusion and dis-agreement among experts about its definition. Nanotechnology is anumbrella term used to define the products, processes, and properties atthe nano/micro scale that have resulted from the convergence of the physi-cal, chemical, and life sciences.

The National Nanotechnology Initiative (NNI) defines nanotechnologyas research and development at the atomic, molecular, or macromolecularlevels in the sub–100-nm range (w0.1–100 nm) to create structures, devices,and systems that have novel functional properties. At this scale, scientistscan manipulate atoms to create stronger, lighter, and more efficient mate-rials (‘‘nanomaterials’’) with tailored properties [3–5]. In addition to thenumerous advantages provided by this scale of miniaturization (over theirconventional ‘‘bulk’’ counterparts), quantum physics effects provide addi-tional novel properties of nanomaterials [3–5].

For instance, the new properties taken on by nanomaterials can be under-stood qualitatively starting from a consideration of large-scale semiconduc-tors. Quantum law dictates that if energy levels within atomic structures areseparated by small amounts of energy, they may be treated as if they werenot separated by any energy amount at all. This description works wellfor semiconductor crystals with large numbers of atoms and physical dimen-sions much greater than 10 nanometers; however, for nano-sized structures,the energy levels are separated by enough energy that the addition or sub-traction of one atom or electron to the crystal will change the energy ofthe bandgap measurably. When a semiconductor crystal has discrete statesit can be defined as a quantum dot (Q-dot); this is when it takes on usefuland interesting properties.

Quantum mechanics additionally dictates that only two electrons can ex-ist at any one energy level. The result is that in any crystal, electrons willstart filling the lowest energy levels first and continue to fill levels with higherenergies until no more energy levels remain without electrons.

An exciton is the term used to describe the electron-hole pair createdwhen an electron leaves the valence band and enters the conduction band.Excitons have a natural physical separation between the electron and thehole that varies from substance to substance. This average distance is calledthe exciton Bohr radius. In a large semiconductor crystal, the exciton Bohrradius is small compared with the crystal, and the exciton is free to wanderthroughout the crystal. In a Q-dot, the exciton Bohr radius is on the order ofthe physical dimension of the dot or smaller; thus, the exciton is confinedwithin the dot. This second set of conditions is called quantum confinement,which is synonymous with having discrete, rather than continuous, energylevels. By definition, Q-dots are in a state of quantum confinement. The dis-tinct emission spectra of Q-dots yield useful properties and numerous appli-cations (see later discussion).

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Some experts consider the NNI definition of nanotechnology overly rigid,emphasizing instead the continuum of scale from the nanoscale to the mi-croscale [4–8]. According to them, the NNI definition excludes numerousdevices and materials of micrometer dimensions, a scale that is includedwithin the definition of nanotechnology by many nanoscientists [4,6,7].

The federal government also is grappling with the definition of nanotech-nology. Government agencies, such as the US Food and Drug Administra-tion (FDA) and the Patent and Trademark Office (PTO), use a rigiddefinition based on a scale of less than 100 nmda definition originally pro-posed by NNI [9,10]. This definition presents difficulties for understandingnanopatent statistics [7] and for the proper assessment of the scientific, legal,environmental, regulatory, and ethical implications of nanotechnology.

This problem exists because nanotechnology represents a cluster of tech-nologies, each of which may have different characteristics and applications[8,11,12]. Moreover, the size limitation of less than 100 nm is rarely criticalto a drug company from a formulation or efficacy perspective, because thedesired or ideal property (eg, improved bioavailability, reduced toxicity,lower dose, enhanced solubility) may be achieved in a size range greaterthan 100 nm.

Hence, the size limitation imposed by the NNI and adopted by other en-tities should be revised, especially with respect to nanomedicine. Similarly,the PTO’s flawed definition of nanotechnology, which is essentially thesame as that of the NNI, has resulted in a skewed preliminary classificationsystem, particularly in reference to nanomedicine and bionanotechnology-related inventions.

To add to this confusion, experts point out that nanotechnology is notnew technology. For example, nanoscale carbon particles (‘‘high-tech sootnanoparticles’’) have been used as a reinforcing additive in tires for morethan a century. Similarly, protein vaccines fall within the NNI definitionof nanotechnology. In fact, the scale of many biologic structures is similarto components involved with nanotechnology. For example, peptides aresimilar in size to Q-dots (w10 nm), and some viruses are the same size asdrug-delivery nanoparticles (w100 nm). Hence, most of molecular medicineand biotechnology may be considered nanotechnology.

A more appropriate and practical definition of nanotechnology, uncon-strained by size, was proposed by Bawa and colleagues [13]:

‘‘The design, characterization, production, and application of structures,devices, and systems by controlled manipulation of size and shape at the

nanometer scale (atomic, molecular, and macromolecular scale) that pro-duces structures, devices, and systems with at least one novel/superior char-acteristic or property.’’

Although the definition is arbitrary, industry and governments are clearlybeginning to envision nanotechnology’s enormous potential. The process ofconverting basic research in nanotechnology and nanomedicine into

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commercially viable products may be long and difficult, but governmentsacross the globe are impressed by its potential and are staking their claimsby doling out billions of dollars, euros, and yen for research. Internationalrivalries are growing [11]. Political alliances and battle lines are beginning toform. Numerous novel nanomedicine-related applications are under devel-opment or nearing commercialization [3,4,12]. The US National ScienceFoundation predicts that by 2015, the annual global market for nano-related goods and services will top $1 trillion, making it one of the fast-est-growing industries in history [11,13]. According to a recent report [14],governments, corporations, and venture capitalists spent almost $10 billionon nanotechnology research and development (R&D) globally in 2005.Emerging nanotechnology was incorporated into more than $30 billion dol-lars of manufactured goods. This report predicted that by 2014, $2.6 trillionin global manufactured goods may incorporate nanotechnology (w15% oftotal output).

Although nanotechnology is characterized by distinctively new technolo-gies, such as scanning probe microscopy and nanolithography, a recent LuxResearch report [15] refuted the popular notion that nanotechnology is a dis-tinct industry or sector, instead considering it to represent a set of tools (eg,scanning probe microscopy) and processes (eg, nanolithography) for manip-ulating matter that can be applied to virtually all manufactured goods. Sim-ilarly, we caution against envisioning a ‘‘nanotechnology market’’ per se.Instead, one should focus on how nanotechnology is being exploited acrossindustry value chains, from basic materials to intermediate products to finalgoods. We believe that most nanotechnology-related products developed inthis decade will remain within existing markets or established sectors andthus, will not be marketed as nanoproducts.

Federal funding and the National Nanotechnology Initiative

The passage of the 21st Century Nanotechnology Research and Develop-ment Act, which authorized $3.7 billion in United States federal fundingfrom 2005 through 2008 for the support of nanotechnology R&D, has fu-eled the fervor over nanotechnology. This legislation resulted in the creationof the National Nanotechnology Coordination Office, which is responsiblefor the funding of various federal nanotechnology initiatives and the crea-tion of R&D centers in academia and government. Currently, more than50 institutes and centers are dedicated to nanotechnology R&D. For exam-ple, the National Science Foundation has established the National Nano-technology Infrastructure Network, composed of 13 university sites thateventually will form an integrated nationwide system of user facilities tosupport research and education in nanoscale science, engineering, andtechnology. Similarly, there are now more than 15 government agencieswith R&D budgets dedicated to nanotechnology. In short, in the UnitedStates, nanotechnology is poised to become the largest government science

809RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

initiative since the space race. Furthermore, federal support for nanotech-nology research does not seem to be losing any momentum. In his 2006State of the Union address, President George Bush highlightednanotechnology:

‘‘First, I propose to double the federal commitment to the most criticalbasic research programs in the physical sciences over the next 10 years.

This funding will support the work of America’s most creative minds asthey explore promising areas, such as nanotechnology, supercomputing,and alternative energy sources.’’

Nanomedicine

What is nanomedicine?

Nanomedicine has been defined as ‘‘the monitoring, repair, construction,and control of human biological systems at the molecular level, using engi-neered nanodevices and nanostructures’’ [4]. Therefore, nanomedicineadopts the concepts of nanoscale manipulation and assembly to applicationsat the clinical level of medical sciences. In a broad sense, nanomedicine is theapplication of nanoscale technologies to the practice of medicine. It is usedfor the diagnosis, prevention, and treatment of disease and to gain anincreased understanding of complex underlying disease mechanisms. Al-though nanotechnology is an established discipline, commercial nanomedi-cine (with its broad range of ideas, hypotheses, concepts, and undevelopedclinical devices) is still at a nascent stage of development.

For example, there are many nanodevices (eg, Q-dots, dendrimers) (Figs.1–4) that are widespread and broadly marketed, but have yet to find theirway into a wide range of clinical devices. This is a consequence of the ex-tremely complex and demanding requirements of clinical trials by theFDA, which can take years before a product makes the long trek from a con-cept in the laboratory to a commercially viable medical product for theconsumer.

Fig. 1. Structure of dendritic drug-delivery vehicles. (Courtesy of Dendritic Nanotechnologies

Inc., Mount Pleasant, MI; with permission.)

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Currently, nanomedicine involves detection of particles; drug deliverysystems, emulsions, and carriers for delivering vaccines; and nanofabricatedbiomaterials with unusual properties of strength, hardness, reduced friction,and improved biocompatibility. More exotic concepts (eg, nanomachinesthat could move through the body, troubleshooting and repairing tiny brainor cardiovascular lesions) lie in the future.

Fig. 2. Dendritic NanoTechnologies’ vehicle for drug delivery/gene silencing. Promising nano-

particles: researchers are working to convert dendrimers like these into useful drug-delivery

tools. Dendrimers are already used widely in the laboratory. Qiagen’s Superfect DNA transfec-

tion reagent is a dendrimer whose positively charged surface binds the nucleic acid’s negatively

charged phosphate backbone. siRNA, silencing RNA. (Courtesy ofDendritic Nanotechnologies

Inc., Mount Pleasant, MI; with permission.)

Fig. 3. Structure and applications of Q-dots. (Courtesy of Evident Technologies, Inc., Troy,

NY; with permission.)

811RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

Commercialization prospects

Early forecasts for nanomedicine commercialization are encouraging(Box 1).

Will these advances in the laboratory result in viable commercial prod-ucts that benefit society or will certain bottlenecks and unforeseen issuesprevent their introduction to the marketplace [9,10]?

Several variables will determine whether advances in the laboratory willtranslate into a wide range of opportunities for the consumer. Multiple chal-lenges confront the commercialization of nanomedicine, including

� Large-scale production challenges� High production costs

Fig. 4. Q-dots for drug delivery. (Courtesy of Evident Technologies, Inc. Troy, NY; with

permission.)

Box 1. Potential of the nanomedicine market

‘‘By 2014, 16% of goods in health care and life sciences (by rev-enue) will incorporate emerging nanotechnologies.’’ [3]

‘‘Sales of nanomaterials for use in nanobiotech applicationsgenerated revenues of $750 million in 2004.projections for2011 are more than $2 billion.’’ [4]

‘‘Venture funds are preferentially going to nanobiotechnology,with 52% of the $900 million in venture capital funding fornanotechnology in 1999 to 2003 going to nanobiotechnologystartups.’’ [5]

‘‘The market for nanobiotechnology has existed for only a fewyears, but it is expected to exceed $3 billion by 2008, reflectingan annual growth rate of 28%.’’ [6]

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� The public’s general reluctance to embrace innovative medical technol-ogy without real safety guidelines� A scarcity of venture funds� Few near-term commercially viable products� A well-established micrometer-scale industry� The pharmaceutical industry’s reluctance to embrace nanomedicine� Confusion at the PTO (with respect to the burgeoning number of patentapplications) and FDA (with respect to safety guidelines)� Absence of clear regulatory guidelines

The nanomedicine ‘‘land grab’’ and its impact on commercialization

Significance of patentsPatents are critical to the nanomedicine revolution. When investors in

nanomedicine or pharmaceutical companies consider the merits of their in-vestment, patent issues are one of the most important items that they review.There also is ample evidence that companies, start-ups, and universities areascribing ever-greater value and importance to patents. Increasingly, theyare willing to risk a larger part of their budgets to acquire, exercise, and de-fend patents.

Patents are essential to start-ups and smaller companies because theymay help in negotiations over infringement during competitive posturingwith larger corporations. Patents may also protect the clients of a patentowner because they may prevent a competitor from infringing or replicatingthe client’s products made under license from the patentee. Moreover, pat-ents provide inventors’ credibility with their backers, shareholders, or ven-ture capitalistsdgroups who may not fully understand the science behindthe technology. For a start-up company, patents are a means of attractinginvestment and validating the company’s foundational technology. There-fore, start-up companies aggressively seek patents as a source of significantrevenue. They cite the potential for licensing patents and the power to con-trol emerging sectors of nanotechnology as major reasons for seeking pat-ents on nanotechnology-related technologies [7].

Experts agree that ‘‘patent awareness’’ (ie, the knowledge that patents areintangible property that can be obtained and lost) is central to any businessplan or strategy [15]. Few venture capitalists are likely to support a start-upthat relies on trade secrets instead of patents, and patents generally precedefunding from a venture capital firm. In short, investors are unlikely to investin a start-up that has failed to construct adequate defenses around its intel-lectual property by obtaining patents on its technology.

Nanomedicine patentsFor more than a decade, all of the world’s major patent offices have faced

an onslaught of nanomedicine-related patent applications [7,8,13,16–21].This situation can only worsen as more applications are filed and pendency

813RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

rates skyrocket further. As companies develop products and processes andbegin to seek commercial applications for their inventions, securing validand defensible patent protection will be vital to their long-term survival.In the decades to come, with nanomedicine maturing and promised break-throughs accruing, patents will generate licensing revenue, provide leveragein deals and mergers, and reduce the likelihood of infringement. The devel-opment of nanomedicine-related products, which is extremely research in-tensive, will be hampered significantly in the absence of the marketexclusivity offered by a United States patent.

The patent land grabThe Bayh-Dole Act of 1980 will assist nanomedicine-related companies in

the same way that it helped biotechnology start-upsdby promoting thetransfer of university-owned patents funded by government grants to theprivate sector. Because of the potential market value of these products(Box 2), researchers, executives, and patent lawyers are making an effortto obtain broad protection for new nanoscale polymers and materials thathave applications in nanomedicine. Therefore, a sort of nanomedicine ‘‘pat-ent land grab’’ is in full swing by ‘‘patent prospectors’’ as start-ups and cor-porations compete to secure broad patents during these critical early days[7,13,16–20,22–30].

These patent prospectors are confronted with an overburdened PTO [27],which historically has been slow to react to new technologies, such as bio-technology and software [7,8,13,16,23,29–37]. In fact, the entire UnitedStates patent system is under enormous scrutiny and strain [29–33,36,38]as the PTO continues to struggle with the evaluation of nanotechnology-related patent applications [7,8,12,13,15–20,23,25,29,39–44]. Therefore,‘‘the jury is out’’ as to whether the nanomedicine industry will thrive (likethe information technology industry) or become burdened (like the radiopatent deadlock) [28]. However, patent grants in nanotechnology and nano-medicine-related inventions are likely to continue at a pace that is almostsynchronous with funding [7,8,13,16–21]. This is true on an internationalas well as a national scale.

Nanomedicine patent thicketsAccording to a recent report from Lux Research [29], almost 4000 United

States nanopatents have been issued as of late March 2005, with another1777 patent applications pending. This report concluded that nanoscienceresearchers around the world are steadily filing patents with the hope of cre-ating tollbooths against future product development. Because there has beenan explosion of overlapping and broad patent filing on nanomaterials, it isprobable that companies that want to use these building blocks in productswill be forced to license patents from many different sources in order to im-plement their inventions. The report focused on five fundamental nanoma-terials: carbon nanotubes, dendrimers, fullerenes, nanowires, and Q-dots.

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The study identified carbon nanotubes and Q-dots as of particular concern.The report noted that although fullerenes and nanowires are mostly free ofoverlapping patent claims, the other categories are quickly attracting patentapplications. For example, the study found that a large number of patentclaims for dendrimers have been assigned to Dendritic Nano-Technologies,

Box 2. Nanomedicine technologies and techniques that can beprotected by a United States patent

BiopharmaceuticsDrug delivery

Drug encapsulationFunctional drug carriers

Drug discoveryImplantable materials

Tissue repair and replacementImplant coatingsTissue regeneration scaffolds

Structural implant materialsBone repairBioresorbable materialsSmart materials

Implantable devicesAssessment and treatment devices

Implantable sensorsImplantable medical devices

Sensory aidsRetina implantsCochlear implants

Surgical aidsOperating tools

Smart instrumentSurgical robots

Diagnostic toolsGenetic testing

Ultrasensitive labeling and detection technologiesHigh throughput arrays and multiple analyses

ImagingNanoparticle labelsImaging devices

Understanding basic life processes

Courtesy of Neil Gordon PE, MBA, and Uri Sagman, MD, Montreal, Quebec,Canada.

815RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

Inc. (Mount Pleasant, Michigan). It also noted that Q-dot patent claimstend to cover the materials themselves rather than specific applications,that the patent situation for using carbon nanotubes in electronics looks‘‘messy,’’ and that ‘‘the common assumption that carbon nanotube patentsare both numerous and overlapping across all important application cate-gories is incorrect.’’ Although some dominant or pioneering patents on car-bon nanotubes will expire in the near future, a classic ‘‘patent thicket’’ seemsto be developing in the area of single-walled carbon nanotubes [26], wherecompanies, such as IBM (White Plains, New York), NEC Corporation(Tokyo, Japan) [7], and Carbon Nanotechnologies, Inc. (Houston, Texas)[26] are likely to stake out their claims aggressively. However, to analyzethe perceived patent thicket in carbon nanotube technology, a detailed legalreview of the claim set (from the patents in the thicket) may be necessarybefore substantial investment in commercialization is made [45]. For exam-ple, carbon nanotubes are a subject of extensive research activity, even at theuniversity level. In fact, academia has become increasingly aggressive in pat-enting its nanomedicine-related research.

Patent thickets are broadly defined in academic discourse as ‘‘a dense webof overlapping intellectual property rights that a company must hack its waythrough to actually commercialize new technology’’ [46–49]. Such patentthickets, as a result of multiple blocking patents, naturally discourage andstifle innovation [46]. Claims in such patent thickets have been characterizedas ‘‘often broad, overlapping and conflictingda scenario ripe for massivepatent litigation battles in the future’’ [23]. Therefore, business plannersand patent practitionersdnamely, patent lawyers and patent agentsdshould steer company researchers away from such potential patent thickets.They may also need to analyze the patent landscape to gauge the ‘‘whitespace’’ opportunities (no overlapping patents) before R&D efforts, patentfiling, or commercialization activities.

Patent battles aheadThe aggressive mentality described above has produced overlapping pat-

ents, and the race to patent anything ‘‘nano’’ has created a flood of undulybroad nanopatents because broad patents generally are awarded for pio-neering inventions.

Clearly, such a proliferation of unduly broad patents will produce patentthickets that will require litigation to sort out, especially if sectors of nanome-dicine become financially lucrative. Given such a patent landscape, expensivelitigation is as inevitable as it was with the biotechnology industry where ex-tensive patent litigation resulted once the products became commercially suc-cessful. In most of the patent battles, the larger entity with the deeper pocketswill rule the day, even if the brightest stars of innovation are on the other side.In the future, the nanomedicine start-ups will become attractive acquisitionsfor larger companies because takeover generally is a cost-effective alternativeto litigation. This situation is all too familiar to business and patent

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communities. It leads to higher costs to consumers (if and when products arecommercialized) [7], while deterring the innovation process itself [27]. Fur-thermore, most experts agree that the stage is set for a wave of cross-licensingagreements by start-ups. Bundles of intellectual property for specific nano-medicine applications will be licensed by groups of large corporations.

Generally, when the total number of owners of conflicting intellectualproperty is small, cross-licensing has been the answer; however, when thenumber of owners of conflicting intellectual property is large, the transac-tion costs of cross-licensing may be too great. At this point, this multiple-party patent thicket problem may be solved by the cooperative formationof patent pools by technologically competing entities. Apart from this, otherstrategies are available to scientists and nanomedicine companies to navi-gate patent entanglements [25].

Ultimately, companies introducing new products to the market will faceconsiderable uncertainty regarding the validity of broad and potentiallyoverlapping patents held by others. The ongoing land grab will worsen theproblem for companies striving to develop commercially viable products.In fact, nanomedicine start-ups may soon find themselves in patent disputeswith large, established companies, as well as between themselves. Therefore,it is critical that reforms be undertaken at the PTO to ensure a better balancebetween innovation and competition [32,33,38,50], particularly in the nano-medicine arena. Otherwise, cursory patent examination at the PTO and theresultant issuance of invalid nanomedicine patents will generate a crowded,entangled patent landscape with few open-space opportunities for commer-cialization. If such a dismal patent climate persists, investors are unlikelyto invest in risky efforts to commercialize nanomedicine. For them, compet-ing in this high-stakes patent game may prove too costly. This patent thicketproblem in nanomedicine may prove to be the major bottleneck to viablecommercialization, negatively affecting the whole nanomedicine enterprise.

Long-term goals of nanomedicine

The National Institutes of Health Roadmap for the Twenty-FirstCentury

Although exciting in its own right, the present status of nanomedicine isonly a milestone on the road to introducing truly innovative technologies.These will come about over a period measured in decades, given the com-plexity of clinical trials and the hesitancy with which radical technologiesare considered and adopted.

To move nanomedicine forward, the ‘‘National Institutes of Health(NIH) Roadmap’’ was recently proposed to address the roadblocks andknowledge gaps that constrain progress in biomedical research. The road-map will bring together many NIH Institutes and Centers to focus and con-solidate research and development in nanomedicine.

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NIH Roadmap funding will be allocated for the following three pro-grams (http://www.nih.gov/):

New Pathways to Discovery, a research program to pursue a comprehen-sive understanding of the body’s cells and tissues and the operation ofcomplex biologic systems using the combined tools of structural biology,molecular libraries, imaging, bioinformatics, and computational biology

Research Teams of the Future, which will focus on interdisciplinary,high-risk research through public–private partnerships

Re-engineering the Clinical Research Enterprise, which will strive to ad-vance discoveries from research into the clinical realm.

The Roadmap concepts were developed by NIH in consultation with itsprofessional staff and the public to identify and prioritize the most pressingproblems facing medical research. The initiatives were selected because oftheir potential for having the most significant impact on the progress ofmedical research.

Through its Roadmap, NIH aims to accelerate the application of innova-tive basic research to the development of novel strategies of prevention, di-agnostics, and treatments with the eventual goal of transferring these to thepublic domain. Specifically:

Research Centers on Nanomedicine will help scientists to construct syn-thetic biologic devices, such as miniature, implantable pumps for drugdelivery or sensors to scan for the presence of infectious agents or met-abolic imbalances that could signify disease.

Nanomedical approaches will be used to better quantify clinically impor-tant symptoms and outcomes, including pain, fatigue, and quality oflife, that are difficult to measure. New technologies will be developedto measure these self-reported states of health across a wide range ofillnesses and disease severities.

A cadre of NIH clinical research associates will be established and com-posed of community-based practitioners. These individuals will receivespecialized training in clinical research. The aim is to advance the dis-covery process and to disseminate research findings to the community.

A standardized data system, the National Electronic Clinical Trials andResearch (NECTAR) network will be developed to facilitate the sharingof data and resources and augment research performance and analysis.

The NIH Roadmap builds on the progress in biomedical researchachieved through the recent doubling of the NIH budget. It reflects a shiftto adaptive management of the NIH portfolio to enable rapid responsesto emerging needs and opportunities that do not fit clearly within the mis-sion of the traditional grouping of Institutes and Centers.

A unique aspect of the NIH Roadmap is the NIH Director’s PioneerAwards that will target outstanding scientists to pursue ‘‘high risk–high

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reward’’ research. The review process for this new grant mechanism will em-phasize the creativity and scientific potential of the person (rather than theproject), thus providing a new way of supporting individuals who showpromise for making seminal contributions to medical research.

Real benefits of nanomedicine

As envisioned earlier, applications of nanotechnology to medical sci-ences hold a wealth of promises. But ‘‘nano’’ has been promoted so enthu-siastically that the hype may exceed reality, especially given the immenselag time between discovery and actual products in biomedical sciences.According to an SRI Consulting Business Intelligence study, hype in nano-technology (as measured by the number of news articles) outpaced patentsawarded for the past few years, in particular from 1997 to 2002 [16]. Acautionary tale concerns monoclonal antibodies, one of the most signifi-cant scientific developments of the latter twentieth century. Discoveredin 1975 [51], antibodies were widely believed to hold great promise as cancertherapeutics, yet the early years of discovery were marked by many failuresin clinical trials. It was only after billions of dollars in research andmany frus-trations that successful antibody products appeared 20 years later.

Nanomedicine is even more problematic because its wide scope is full ofpotential, yet it is still beset by many fundamental questions. Given these ca-veats, the recognizable benefits of nanomedicine are in the area of materialsthat can act as carriers for medicines and tagged compounds for visualizingcancers and other lesions.

Areas of potential development

We expect that in the coming years significant research will be under-taken in the following areas of nanomedicine:

Synthesis and use of novel nanomaterials and nanostructures (eg, lessantigenic)

Biomimetic nanostructures (synthetic products developed from an under-standing of biologic systems)

Analytic methods and instruments for studying single biomoleculesDevices and nanosensors for early point-of-care detection of diseases and

pathogens (eg, polymerase chain reaction–coupled micro/nano-fluidicdevices)

Identification of novel biologic targets/receptors/ligands for imaging,diagnosis, and therapy (eg, for cancers and for neurodegenerativeand cardiovascular diseases)

Construction of multifunctional biologic nanostructures, devices, andsystems for diagnosis and combined drug delivery (theranostics)

Nanotechnology for tissue engineering (nanostructured scaffolds) andregenerative medicine

819RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

Fabrication of noninvasive in vivo analytic nanotools with improvedsensitivity and resolution for molecular imaging and for studyingpathologic processes in vivo

Stimuli-sensitive nanodevices and physically targeted treatments

Specifically, in the drug-delivery arena, nanotechnology is poised to de-liver to the market evolutionary and revolutionary products [4,12]. Someproducts could be available immediately, whereas others will appear inthe distant future and include:

Miniaturized nanofluidic devices and systems that transport fluids moreefficiently to the site of delivery, preventing turbulence and mixing (be-cause fluids move with laminar flow through micro/nanochannels)

More efficient site-specific or precision targeting by way of nanodrugs, re-sulting in with reduced systemic side effects and better patientcompliance

Close-looped drug delivery nanodevices and implants containing sensors(to monitor biomolecules) and drug reservoirs (for precise delivery) onthe same chip

Microsurgical devices, molecular motors, or nanobots that are capable ofnavigating throughout the body to repair damaged sites, destroytumors or viruses, and even perform gene therapy

Nanoparticulate drug delivery vehicles [52] would allow faster drug ab-sorption, controlled dosage releases, and shielding from the body’s immunesystemdenhancing the effectiveness of existing drugs. Consider this simpleexample: imagine the market share of an over-the-counter pain reliever thatworks 20 times faster than aspirin.

Researchers are also investigating novel treatments using nanoparticles,such as dendrimers, as delivery devices to insert genes into cells.

Nanotechnology is being applied to the drug discovery and developmentprocess as well. The drug discovery process is time consuming and expensive(8–14 years at a cost of w$1 billion dollars). Nanotechnology will result ina reduction of the cost of drug discovery, design, and development. In ad-dition, nanotechnology will enhance the drug discovery process itselfthrough miniaturization, automation, speed, and reliability of assays. Thiswill result in the faster introduction of new, cost-effective products to themarket. For example, nanotechnology can be applied to current microarraytechnologies, exponentially increasing the hit rate for promising compoundsbeing screened as candidates for the pipeline of drug development. Inexpen-sive and higher throughput DNA sequencers based on nanotechnology canreduce the time for drug discovery and diagnosis.

In the nanodiagnostics area, much of the research has been focused onbiochips, devices containing numerous biologic sensors. Nanotechnologyhas been proposed to increase the density of such sensors on the biochipsand to provide alternative detection mechanisms.

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Nanomedicine also aims to learn from naturedto understand the struc-ture and function of biologic devices and to use nature’s solutions toadvance science and engineering. This approach is referred to as ‘‘biomimi-cry.’’ Evolution has produced an overwhelming number and variety ofbiologic devices, compounds, and processes that function at the nanometeror molecular level and that provide performance that is unsurpassed bysynthetic technologies. When nanotechnology is combined with molecularbiology, the possible applications at this frontier are widespread, soundinglike the stuff of science fiction. Nanomedicine can be characterized as a prim-itive technology that takes advantage of the properties of highly evolvednatural products, such as nucleic acids and proteins, by attempting to har-ness them to achieve new and useful functions at the nanoscale. The con-struction principles used in this field often originate in biology, and thegoals often are biomimetic or aimed at the solution of long-standingresearch problems. The concept of self-assembly is at the heart of theapproaches in this field. Self-assembly of ordered elements is a definingproperty of life. Nanomedicine attempts to exploit the self-assembly and or-dered proximity of nanoscale structures found in biology [23].

Selected categories of nanomedicine

Basic nanomedicine for cellular and molecular dynamics in living cells

The analysis of dynamic cellular processes has been pursued throughoutthe history of modern cell biology, using a variety of techniques by whichcells and tissues were disrupted, their content partitioned, and tagged com-ponents separated and delineated [53]. The ‘‘golden age’’ of molecular cellbiology saw the exploitation of radioactive isotopes in the use of a varietyof cell separation technologies [54]. But classic biochemical studies maynow be superseded by advances in nanosensor development, which willopen up new possibilities for examining metabolic processes in living cellsand organisms.

One of the prime tools for investigation in cell biology has been organicfluorescent compounds; over the last 3 decades, organic chemists have syn-thesized a wide array of choices. Nonetheless, these molecules leave much tobe desired. They frequently suffer from broad spectral overlap, photobleach-ing, difficult conjugation chemistry, poor aqueous solubility, and high cost.The recent development of nanocrystals promises a alternative superior toorganic dyes.

Deciphering the intricacies of plant metabolomics (http://www.metabolomics.bbsrc.ac.uk/) is proving a major challenge that can be ad-dressed using nanosensor technologies. Fehr and colleagues [55] proposedthat protein-based nanosensors for metabolites will allow the determinationof cytosolic and subcellular metabolite levels in real time using fluorescence-based microscopy, providing essential information for the construction of

821RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

cellular and whole-plant models of metabolism. A major challenge in the fu-ture will be the application of these nanosensors to quantify metabolitelevels in plant cells and tissues.

Quantum dotsQ-dots figure prominently in the investigation of dynamic processes in

living systems. Their properties have been reviewed extensively [56]. Thesecolloidal semiconductors are single crystals whose size and shape can becontrolled precisely, which determines their absorption and emission prop-erties. Thus, the investigator can precisely design fluorophores whose emis-sion is related directly to their size (so called ‘‘quantum confinement’’), suchthat the Q-dot will emit photons in a tightly defined color range. Even singlemolecules can be tracked. The specificity of Q-dots may be realized, for ex-ample, by coating them with streptavidin and then conjugating them to a bi-otinylated antibody. In this state, the Q-dot can bind to a specific cellularreceptor or other cellular target. In addition to a recognition moiety, differ-ent functionalities can be added to individual Q-dots, resulting in multipo-tent probes. By coating Q-dots with natural peptides, it is possible toproduce particles with excellent biocompatibility, colloidal properties, andphotophysics. Q-dots possess the striking property of resistance to photo-bleaching over long periods of time, making them useful for long-term,three-dimensional studies. Moreover, they are extremely bright, displaying10 to 20 times the emission level of organic fluors [57].

According to Pinaud and colleagues [58], although Q-dots are not theperfect fluorophores and much more research will be required to improvetheir photophysics and obviate their cytotoxicity, these versatile entitiesalready have found their place in the repertory of bioimaging tools. Theirchoice as long-term, high-sensitivity, and multicontrast imaging agents ofmolecular dynamics in biologic samples is assured.

Fluorescence resonance energy transferFluorescence resonance energy transfer (FRET) between a donor and an

acceptor molecule provides qualitative information about distance andquantitative information about the kinetics of changes in distance [59]. Lo-oger and colleagues [60] designed a panel of metabolite nanosensors by en-gineering protein chimeras of ligand-binding domains with fluorescentprotein FRET donor–acceptor pairs. These sensors perform in living cellsand when manipulated through genetic engineering permit visualization ofa variety of uptake and transport processes. By targeting the sensors to dif-ferent subcellular locations, a novel high-capacity glucose transport path-way was identified in the lumen of the endoplasmic reticulum (ER). Fehrand colleagues [61] measured ER transport of glucose, using FRET-basednanosensors targeted to the cytosol or the ER lumen of cultured cells.They identified a high-capacity glucose transport system on the ER

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membrane, consistent with the hypothesis that glucose export from hepato-cytes occurs by way of the cytosol by a yet to be characterized set of proteins.

Deuschle and colleagues [62] constructed a family of genetically encodedmetabolite sensors using bacterial periplasmic binding proteins (PBPs) fusedto protein fluorophores. The ligand-induced conformational change ina PBP allosterically regulates the relative distance and orientation ofa FRET-compatible protein pair. Ligand binding produces a signal, provid-ing a reagent for in vitro and in vivo ligand study. Sensors with a higherFRET signal change are needed to expand the dynamic range and allow vi-sualization of subtle analyte changes under high noise conditions. High-response sensors for glucose and glutamate, ligands of great clinical interest,may be manipulated to produce reagents for the study of ligand-dependentallosteric signal transduction mechanisms.

Freeman and colleagues [63] developed optical detection tags for use incellular and whole animal imaging assays. These detectable, surface-en-hanced Raman scattering nanotags are silica nanoparticles coated withgold. A family of unique tags can be generated by varying the Raman activemolecule adsorbed on the nanoparticle, thus allowing multiplexed detectionto be performed. Because the tags are excited in the far red or near infraredand can be detected with low-cost instrumentation, they are ideal for per-forming assays in tissue and whole blood.

DendrimersDendrimers are a major architectural class of nanoscale chemical poly-

mers [64]. The term describes a large, synthetically produced preciselydefined polymer in which the atoms are arranged in many branches and sub-branches radiating out from a central core [65].

Dendrimers are built from a starting atom, such as nitrogen, to which car-bon and other elements are added by a repeating series of chemical reactionsthat produce a spherical branching structure. As the process repeats, succes-sive layers are added, and the sphere can be expanded to the size required bythe investigator. The result is a spherical macromolecular structure whosesize is similar to albumin and hemoglobin, but smaller than such multimersas the gigantic IgM antibody complex. By manipulating the chemistry ofdendrimers, the geometry and properties of their structure can be altered toperform a vast array of functions, including acting as MRI contrast agents.

A new class of dendrimers with large proton relaxation enhancementsand high molecular relaxivities has been built from the polyamidoamineform of Starburst dendrimers. Free amines of the polyamidoamine havebeen conjugated to the chelator 2-(4-isothiocyanatobenzyl)-6-methyl-diethy-lenetriaminepentaacetic acid [66] to make dendrimers that have importantapplications. By altering the size of the dendrimers, their properties of elim-ination through excretion can be changed profoundly, with the consequencethat a range of patterns of localization in kidneys, lymphatics, liver, andblood pool can be specified.

823RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

This new class of contrast agents has the potential for extensive applica-tions in MRI. By the same rationale, dendrimers can be engineered fornano-based drug delivery. Dendrimers can be designed to the appropriatesize to encapsulate a drug, allowing for optimum delivery. The degree ofencapsulation can dictate the rate of release in a controlled manner.

The nanodimensions of the dendrimers can be specified so as to fit a spe-cific receptor, thereby targeting delivery of the drug. Although traditionaldrug delivery is monovalent, dendrimers can be engineered to carry a largenumber of drug molecules on their spherical exteriors in such a fashion thatinteraction with the receptor-studded cellular membrane mimics the naturalbinding of a large viral entity to the target cell.

Nano-liposomesMoghimi and Agrawal [67] reviewed the potential of lipid-based nanosys-

tems, such as nanoemulsions, lipid-core micelles, and small unilamellar ves-icles. These represent tantalizing candidates for improving drug solubilityand targeting following parenteral administration. Important advances arebeing made with such complexes in combating metastasis of cancerous tis-sues. Strategies under consideration include exploitation of angiogenic tu-mor vasculature, combination chemotherapy, and endogenous-triggeredactivation and release of encapsulated lipid prodrugs. Other liposome ap-proaches include treatment of macrophage infections through exploitationof their clearance mechanisms, gene transfer using cationic lipid vectors,and stimulation of immune responses to antigens with the aid of liposomecomplexes that behave as self-adjuvants.

Nano-oncology

Diagnosing, treating, and following the progress of therapy for individualmalignancies are the principal goals of oncologists for which nanotechnol-ogy offers solutions. The ability to shape molecules with great precision isopening the door to a new generation of drugs, imaging agents, and diag-nostics. In 2004, the National Cancer Institute committed $144 million infunding for interdisciplinary research in cancer-directed nanotechnology[68]. Because nanotechnology offers more than just a tool, but rather a per-vasive concept, it promises to dominate the entire enterprise of cancerdiagnostics and therapeutics. Already, a half-dozen nanoparticles-based im-aging and therapeutic agents are in various stages of development (Table 1).

Oncological diagnostic applicationsNanotechnology provides tools for developing personalized medical

treatments by tracking and identifying receptors and other cell surface pro-teins specific to individual tumor cells. For example, iron oxide nanopar-ticles coupled to the therapeutic antibody trastuzumab have been targetedand bound to the HER-2/neu cell membrane receptor, eliciting detectable

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changes in ultrasound responses from human breast cancer cells [69]. Pres-ence of the receptor is the critical factor predicting favorable response totrastuzumab therapy. Using receptor-positive and -negative cell lines,HER-2/neu–positive SKBR-3 cells tagged with trastuzumab conjugatediron oxide particles could be distinguished from those that have not demon-strated particle binding. These findings serve as proof-of-concept data forthe development of a diagnostic test for trastuzumab response in patientswho have breast cancer.

In another approach, Zheng and colleagues [70] used silicon-based nano-wires to electrically detect marker proteins overexpressed in the circulationof patients who had cancer. These devices behave as minute computer chipsanddwhen coated with antibodiesdcan transfer electrical signals from thetarget protein to the antibody, causing a change in the conductance of thenanowire. This signal can be measured, indicating the presence and amount

Table 1

Nanotechnology cancer treatments that are being tested or have been approved

Moving to market

Product

Type of

nanomaterial Phase Indication Company

VivaGel Dendrimer Topical

microbicide

for HIV

Phase 3 StarPharma

MRX-952 Branching block

copolymer

self-assembled

nanoparticulate

formulation of

irinotecan

metabolite

Oncology Preclinical ImaRx

Therapeutics

Abraxane Paclitaxel-albumin

Nanoparticle

Non-small cell

lung cancer,

breast cancer,

others

On market American

Pharmaceutical

Partners

Cyclosertcamptothecin Cyclodextrin

nanoparticle

Metastatic solid

tumors

IND filed Insert

Therapeutics

TNT AntiEpCAM Polymer-coated

iron oxide

Solid tumors Preclinical Triton

BioSystems

Verigene platform DNA-functionalized

gold nanoparticles

Diagnostics On market Nanosphere

INGN-401 Liposome Metastatic

lung

cancer

Phase 1 Introgen

Combidex Superparamagnetic

iron oxide

nanoparticle

Tumor imaging NDA filed Advanced

Magnetics

Abbreviations: IND, investigational new drug; NDA, new drug application.

Data from Service RF. Nanotechnology takes aim at cancer. Science 2005;310:1134.

825RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

of the antigenic protein. Protein markers, including prostate-specific anti-gen, PSA-alpha-1-antichymotrypsin, carcinoembryonic antigen, and mu-cin-1, were detected routinely at femtomolar concentrations. The signalscan be read using instruments that measure electrical conductivity, andarrays containing as many as 200 transistors can be fashioned. This wouldallow the possibility of measuring scores of markers in a single blood sam-ple. These detection systems avoid complex polymerase chain reaction tech-nology or the use of fluorescent probes to detect cancer-related antigens.

Mirkin and colleagues [71] have published extensively on the use of goldnanoparticles to measure the presence of cancer-associated DNA and pro-tein signatures. The gold nanoparticles are coupled to DNA detectors orantibodies and printed as conductivity bridges. When the antigen or signa-ture DNA for a cancer-related marker is present in a sample, it will bind tothe bridge. These molecules can be collected by detector DNAs or anti-bodies labeled with metal nanoparticles, completing an electrical circuit,thereby producing an extremely sensitive response that is up to a milliontimes more sensitive than ELISAs.

Early cancer detection using Q-dots has been the subject of extensivestudies. Kim and colleagues [72] described the use of Q-dots composed ofan inner cadmium tellurium core surrounded by a cadmium selenium layerand capped with an organic compound to make the particles water soluble.When injected into pigs, lymphatic cells cleared the Q-dots and routed themto the lymph nodes. By shining infrared lamps on the skin of the subject an-imals, the lymph nodes could be identified and localized easily because oftheir emission of wavelengths in the infrared range. This technology shouldprove useful for localizing tumors near the skin.

An analogous approach is being considered for localizing deep tumors,far from the surface, using magnetic nanoparticles. Nanoparticles alsohave been used as luminescent probes for optical imaging [73–75] and asmagnetic probes for nuclear MRI [76].

The use of near-infrared luminescent nanoparticles [77,78] for deep tissueoptical imaging was described by Morgan and colleagues [79], who demon-strated the use of nanocrystals (a term synonymous with Q-dots) as an an-giographic contrast agent for vessels supplying a murine squamous cellcarcinoma. The investigators prepared semiconductor nanocrystals ofCdMnTe/Hg coated with serum albumin. Depth of penetration for excita-tion and emission was evaluated by imaging a beating mouse heart throughan intact thorax and after a thoracotomy. The associated temporal resolu-tion and the blood clearance for this contrast agent also have been mea-sured. The nanocrystals showed no significant photobleaching ordegradation after an hour of continuous excitation. The stability of thenanocrystals, together with the temporal resolution of the optical detection,makes them particularly attractive candidates for pharmacokinetic imagingstudies. Moreover, these technologies are associated with equipment coststhat are much lower than competing technologies, such as MRI.

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Dendrimers are under intensive scrutiny for their promise in cancer detec-tion and therapy [80]. In animal models, attaching chemotherapeutic agentsto dendrimers allows delivery of small doses of the drug directly to the can-cer cells, greatly improving survival. Because the dendrimers also were la-beled fluorescently, their movement to the cells could be followed. Thetechnique has been applied only to head and neck squamous cell carcinomain mice; however, trials with bladder and ovarian cancer are planned. Thistechnology may prove significant as an innovative delivery option. Becauseof their small size (w5 nm), dendrimers can cross mucosal barriers and vas-cular pores and can be removed safely from the bloodstream by the kidneys.

Future applications include targeting specific individuals’ genotypes aswell as tracking responses to antineoplastic drugs and modifying them ac-cordingly. Alternatively, some tumors have multiple types of cancer cells,each requiring a different antineoplastic drug. Dendrimers could be usedto detect which types of cells are present and deliver the required chemother-apeutic. Also, they may be able to track how individual cells respond, allow-ing the physician to modify treatments.

Although the dendrimer inclusion particles of Kukowska-Latallo andcolleagues [80] are about eight times the size of dendrimers, efforts are underway to deliver them through the bloodstream and deal with the challenge ofeliminating them from the host.

The use of cantilevers is another area in which nanotechnology has beenapplied to cancer detection [81–84]. These microfabricated silicon devicesare arrayed as projections from a solid support. They are flexible and willbend under stress. Although the size may vary according to protocol needs,typically they are 500 mm long, 100 mm wide, and 1 mm thick. The siliconcantilevers are coated with a gold film, which will bind molecular probes,either protein or nucleic acids. When the nanodevice is immersed in a hybrid-ization buffer, it will bind the complementary molecule. This binding causesa deflection of the cantilever, which can be detected by an optical beam. Thebending can be brought about by DNA–DNA pairing and by protein–pro-tein interactions, such as an antigen binding to a conventional or recombi-nant antibody [85]. The devices have tremendous sensitivity, because anindividual cantilever’s deflection can be observed. Although detection usingoptical methods is a convenient option, Mukhopadhyay and colleagues [86]used piezoresistance to detect DNA samples using DNA probes bound tocantilevers.

Recently, Wee and colleagues [87] reported an electro-mechanical biosen-sor for electrical detection of proteins with disease markers using self-sensingpiezoresistive microcantilevers. Electrical detection, by way of surface stresschanges, of antigen–antibody-specific binding was accomplished througha direct nanomechanical response of microcantilevers. When specific bindingoccurred on a functionalized gold surface, stress was induced throughout thecantilever, resulting in cantilever bending and a concomitant resistancechange in the piezoresistive layer. By coupling antiprostate-specific antigens

827RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

(anti-PSA) with C-reactive protein antibodies on to the cantilever, ex-tremely low concentrations of antigens could be detected. The sensor out-put voltage was proportional to the antigen concentration, establishing thepotential of the technology for clinical malignancy screening. The sameteam designed and fabricated a nanomechanical cantilever for label-free de-tection of PSA with a detection sensitivity of 10 pg/mL [59,88]. The nano-mechanical lead zirconium titanate (PZT) cantilevers used composite layersof Ta/Pt/PZT/Pt/SiO2 on a SiNx supporting layer for electrical self-sensingwithout external oscillators. This method allows PSA proteins to be de-tected by a simple electrical measurement of the resonant frequency change,rather than optically. The resonant frequency shifts because of the specificbinding of the PSA antigen (Ag) to its antibody (Ab), which is immobilizedby way of calixcrown (complex molecules with crown ether functionalitiesused for solvent extraction that possess a cavity where various heavy metalscan bind) self-assembled monolayers on a gold surface deposited on a nano-mechanical PZT cantilever. Theoretic and experimental analysis suggestthat the minimum detectable sensitivity for a resonant frequency shiftdue to a PSA Ag–Ab interaction depends on the dimensions of the nano-mechanical PZT cantilever. These results also demonstrate that the exper-imentally measured resonant frequency shift was larger than that calculatedtheoretically because of the compressive stress of the PSA Ag–Abinteraction.

Treatment modalitiesA variety of nanotech therapeutic modalities is in various stages of devel-

opment. Roby and colleagues [89] developed chemotherapeutic nanopar-ticles composed of a polyethylene glycol/phosphatidyl ethanolamineconjugate. This strategy allowed solubilization of a poorly soluble photody-namic therapy agent, meso-tetratphenylporphine (TPP). The investigatorsconstructed tumor-targeted polymeric micelles in which TPP was encapsu-lated. When coated with an antitumor antibody (2C5), a significantly im-proved anticancer effect of the micelles against murine and human cancercells in vitro was observed following light irradiation. The strategy allowsthe introduction of large amounts of the drug into the cells resulting in sub-stantial killing of the targets.

Kaul and Amiji [90] evaluated a nanoparticle transfection system foradministering chemotherapeutic agents to tumors. Using a reporter systemencapsulated in PEGylated gelatin nanoparticles, they demonstrated 61%transfection efficiency to tumor cells in a mouse model system. The bio-compatible and biodegradable nanoparticles seem to be an effective wayto transmit therapeutic agents into the tumor cells. Other groups alsoare working on multipurpose platforms for detecting and treating cancer;however, they have yet to show that their devices can get out of the blood-stream and later out of the body. Huang and colleagues [91] attachedantibodies to gold nanoparticles, allowing the particles to selectively

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bind to certain cancer cells. The light reflected from these particles revealstheir location; light absorbed by the particles causes them to heat up, de-stroying the targets, but leaving surrounding nonmalignant, healthy cellsunharmed.

Cardiovascular nanomedicine

Cardio-nanomedicine has elicited much excitement from the point ofview of diagnostics as well as that of therapeutics, although FDA-approvednanocardioproducts are not available. The academic and commercial sec-tors have noted these developments with interest as evidenced by a recentmeeting of the American Society of Cardiology (ASC) [92]. According tothe American Heart Association Web site (http://www.americanheart.org),cardiovascular disease remains the leading cause of death in the UnitedStates at approximately 1 million yearly, about twice that of cancer. Throm-bosis, an abnormal clot formation within a vessel, makes up a significantpercentage of all cardiovascular deaths. Consequences of vascular occlusionby thrombi may be catastrophic, including heart attack, stroke sequelae,miscarriage, and paralysis.

Participants at the ASC conference discussed technologies for imagingand drug delivery to individual cells or diseased tissues. Nanoparticle agentshold promise as cardiovascular diagnostic tools. Strategies include MRI ofintravascular thrombi using the imaging agent packaged inside a liquid per-fluorocarbon nanoparticle emulsion. The nanoparticles can be targeted spe-cifically to the thrombus by way of an antibody expressed on the surface ofthe nanoparticle directed against cross-linked fibrin, allowing even smallthrombi to be imaged.

A variety of imaging devices, such as superparamagnetic nanoparticlesand perfluorocarbon nanoparticle emulsions, have been developed for non-invasive MRI [93]. The delivery of local therapy with these nanoparticles,using mechanisms such as contact-facilitated drug delivery, is in the ad-vanced stages of preclinical research. These approaches promise to changethe current medical paradigm of ‘‘see and treat’’ to a ‘‘detect and prevent’’strategy. Designed to target specific epitopes in tissues, these agents are be-ginning to enter clinical trials for cardiovascular applications.

There are numerous proteins whose presence has been implicated asa marker for thrombosis [94–99]. These investigations have driven a searchfor a panel of diagnostic markers. GenTel is one of several microarray com-panies designing multiplex immunoassays to identify a molecular signaturein blood that can be used to aid in early detection and personalized therapy.The company’s platform uses microspots of specific antibodies printed atunique addressable locations as a microarray that binds 10 coagulation-related proteins in blood and subsequently measures their analytical masssimultaneously using a sandwich antibody configuration. The term ‘‘sand-wich’’ describes a classic immunoassay procedure in which an antibody is

829RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

immobilized on a solid surface where it acts as a capture mechanism. In thisconfiguration it can endow a diagnostic procedure with greatly increasedlevels of specificity.

Their assays consist of a so-called ‘‘sandwich ELISA,’’ in which a solidsurface is coated with a first or capture antibody. This module is used toscreen samples from patients, with the antigens binding to the material ofinterest. The second half of the sandwich is a second antibody hooked toa detector molecule, such as a fluorescent molecule or an enzyme. If the tar-get is present in the sample, molecules will bind to the first antibody, and thesecond antibody will bind to the antigen. The detector accompanies the sec-ond antibody so positive samples yield a signal that is detectable by appro-priate reader devices. The system will measure up to 20 proteins in bloodusing a biotinylated detector antibody specific for the protein target anda streptavidin-fluorophore conjugate. GenTel has evaluated many clottingfactors associated with thrombophilia, including matched antibody pairsspecific for prothrombin, factor V, factor VII, factor VIII, factor IX, factorX, and protein C. GenTel demonstrated that they bind their cognate anti-gens without cross-talk (nonspecific binding) to the alternative antigensand that these results are reproducible.

Using the same rationale, angiogenesis in early-stage atherosclerosis canbe imaged by injection of paramagnetic nanoparticles targeted by an anti-body to the avb3 integrins, membrane proteins indicative of neovasculariza-tion [100].

Targeted drug-delivery platforms are being evaluated in which a lipophilicdrug is incorporated into the surface of a liposome containing an antibodybound to its surface. The drug is not released until the liposome binds to thetarget cell. When this occurs, there is exchange of lipid from the liposomewith that of the cell membrane, allowing the drug to selectively enter thecell at a high concentration, thus greatly reducing systemic exposure andcollateral toxicity of the drug.

Nanotechnology tissue engineering of the heart includes investigations ofcultured cardiomyocytes, which were induced to orient themselves in an or-derly fashion on parallel microstrips of laminin-coated elastomeric biode-gradable polyurethane film. This parallel alignment results in moreeffective contraction than that achieved in the absence of this ordering.Moreover, biomaterials can be modified to control vascularization aroundtissue-engineered regeneration materials and to regulate the foreign body re-action to biomaterials. The use of controlled release of proteins and nucleicacids from hydrogel matrices will permit control of vascularization, an es-sential component of viable tissue repair.

Such matrices could transport and deliver anti-inflammatory mediators,such as antisense and RNA interference therapeutics that inactivate macro-phage signaling targets or inflammatory cytokines, thus controlling harmfulinflammatory processes. These studies demonstrate the potential of trans-plantation of tissue-engineered cardiomyocytes for repairing failing hearts

830 MORROW et al

and the need for an integrated strategy to control inflammation and vascu-larization in addition to providing new myocytes.

Malinski [101] used nanosensors to investigate the question of the highrate of cardiovascular disorders among African Americans. Nanosensorsdesigned for measuring nitric oxide (NO) levels in vitro, ex vivo, and invivo were used at the molecular level in a single endothelial cell. The NOnanosensors are based on specifically designed electrically conductive or-ganic materials (porphyrinic molecular metals) that can oxidize NO selec-tively and generate a current proportional to its concentration. Real-timedetection is possible at the level of a single biologic cell or neuron.

NO is a critical signaling molecule generated by NO synthase fromL-arginine and oxygen. Uncoupling of constitutive nitric oxide synthaseleads to overproduction of superoxide (O2

�) and peroxynitrite (ONOO�),two potent oxidants. These investigations showed that African Americanshave an inherent imbalance of NO, O2

�, and ONOO� production leadingto release of radicals and subsequent damage to cardiac muscle, whichmay explain why they are at greater risk for developing cardiovascular dis-eases, such as hypertension and heart failure.

Ligand-directed perfluorocarbon nanoparticles are a platform technologywith diagnostic usefulness across all relevant clinical imaging modalities aswell as local delivery of therapeutics for a wide spectrum of diseases, includingcancer and cardiovascular disease. In cardiovascular disease, nanomedicineapplications based on this novel agent could include recognition and therapyof early atherosclerosis beforemyocardial infarction, discovery of unstable ca-rotid plaques before the onset of stroke, prevention of restenosis following an-gioplasty without impaired vessel healing, and early delivery of thrombolyticenzymes to intravascular thrombi with less risk for adverse events.

Cardiovascular biomaterials developed using nanotechnology must allowfor blood compatibility. Meng and colleagues [102] investigated multiwalledcarbon nanotube-polyurethane composites prepared through a controlledcoprecipitation. Their analysis found that when these structures containedoxygen-functional groups, the carbon nanotubes were dispersed well ina polyurethane composite. The composite surface displayed a significantlyimproved anticoagulant function, suggesting that carbon nanotube-basedmaterials can be used in the implants and medical devices applied inblood-contacting environments.

Ultimately, combined diagnostic and therapeutic nanoparticle formula-tions may allow patients to be characterized noninvasively and partitionedto receive custom-tailored therapy. Moreover, speculative cardiotherapiesusing nanomedicine have been proposed. Grossman (2005) mused aboutFreitas’ [103] suggestion of the possibility of developing ‘‘respirocytes,’’nanoengineered, artificial erythrocytes that could deliver oxygen to tissuesat a much higher rate than naturally occurring biologic red blood cells.These entities could be used to treat diseased or injured patients or, ona much more controversial level, to enhance athletic performance.

831RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

Neurologic nanomedicine

One of the most challenging areas in medical science is the repair of thecentral nervous system (CNS) following trauma [104]. Numerous developingnanotechnology platforms are being brought to bear on this issue, andbroad applications are emerging that may be relevant to other areas of med-icine and physiology. The CNS raises particular challenges because of re-stricted anatomic access due to the complexities of its wiring. Nonetheless,advances in nanochemistry, combined with an expanding understandingof the molecular and anatomic basis of CNS function, are moving forwardat a rate that should soon allow nanotechnology-based therapies to advanceto clinical trials.

Nanotechnology applications are being used to protect the CNS fromfree-radical damage, which plays a significant role in various pathologies, in-cluding trauma and degenerating neurologic disorders. A host of noxiouschemical species, including superoxide, hydroxyl, peroxide, and peroxyni-trite ions, is known to mediate these destructive processes [105]. Therapieshave been developed using fullerines engineered to function as scavengers,such as carbon-60 fullerenols, hydroxyl functionalized derivatives of fuller-enes [106].

Nanosensor technologies are being developed to monitor glutamate levelsinside and at the surface of living cells [107]. These excitatory amino acidsplay a critical role as the major neurotransmitter in the vertebrate CNS,influencing essentially all forms of behavior. Changes in the strength of con-nectivity at glutamatergic synapses in the form of long-term potentiationand long-term depression are believed to be the cellular mechanisms under-lying learning and memory [108]. Moreover, glutamate is also involved inthe neurologic damage occurring in stroke and neurodegenerative disorders[109]. Once released, its rapid removal from the synaptic cleft is critical forpreventing excitotoxicity and spillover to neighboring synapses.

A fluorescent indicator protein for glutamate (FLIPE) was designedusing genetic engineering by fusing the glutamate/aspartate binding proteinybeJ to two variants of the green fluorescent protein. In the presence of li-gands, FLIPEs show a concentration-dependent decrease in FRET effi-ciency. When expressed on the surface of hippocampal neurons, thesensors respond to extracellular glutamate with a reversible concentration-dependent decrease in FRET efficiency. The FLIPE sensors can be usedfor real-time monitoring of glutamate metabolism in living cells, in tissues,or in intact organisms, providing an innovative tool for analysis of metab-olism and for drug discovery in the CNS.

The need for ultrasensitive detection methods is an important issue inbasic and clinical neurosciences [110]. Perhaps the most critical target fordiagnosis is Alzheimer’s disease (AD), a progressive neurodegenerative de-mentia, affecting more than 4 million Americans. A wealth of data [111]has implicated the amyloid beta (A-beta) protein in the etiology of this

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condition. A-beta is a 42-amino acid peptide known to be the monomericsubunit of the large insoluble amyloid fibrils of AD plaques. Moreover,A-beta proteins self-assemble into small soluble oligomers, termed amy-loid-derived diffusible ligands, which are responsible for neurologic dysfunc-tions relevant to memory. The clinical diagnosis of AD can only be made atautopsy. An ultrasensitive method for detection of amyloid-derived diffus-ible ligands potentially could emerge from nanosensor technology.

Nanotoxicology in health and environment research

With nanotechnology R&D rapidly expanding and a trillion dollar im-pact on the world economy forecasted by 2015, concern is increasing overthe putative environmental and health consequences of the widespread dis-semination of these materials. Because of their small size, a large proportionof the atoms that make up a nanoparticle are exposed to the exterior of theparticle and would be free to participate in many chemical processes. Al-though this is one of their most treasured attributes, it could lead to adverseconsequences resulting from their introduction into the environment.

Safety issues in the workplaceConcerns over safety issues are heightened by the fact that the nanotech-

nology workforce is growing rapidly, projected to reach 2 million workersby 2015. At present, the United States spends $1 billion a year on nanotechresearch, but only $39 million of this figure goes for investigations on healthand environmental consequences [68]. The European Commission contrib-utes substantially less, $7.5 million. This phenomenal growth has drivencalls to increase the contribution from both ends of the economic and polit-ical spectrum. For example, both DuPont CEO and Environmental Defensehave editorialized in the Wall Street Journal that the United States shouldspend much moredin the range of $100 million yearlydon the toxicologyof nanotechnology.

Unknown dangersRecently, Maynard and Kuempel [112] drew several pivotal conclusions

from their analysis of available toxicology data. Although few studieshave addressed the toxic effects of nanomaterials in the workplace, carefulplanning must be undertaken when assembling protocols for evaluation inan occupational setting. Studies in humans showed that the deposition ofnanoparticles in the lungs increases with decreasing particle size, and thetoxicity of inhaled insoluble nanomaterials increases with decreasing particlesize and increasing particle surface area. Although emissions of engineerednanoaerosols into the workplace are believed to be low, the significance ofthese findings cannot be assessed without further information on how par-ticle size, chemistry, and structure influence toxicity. Methods to control air-borne nanostructured particle exposure have not been characterizedcomprehensively at small particle diameters. Barlow and colleagues [113]

833RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

provided evidence that carbon black nanoparticles may induce a type IIalveolar epithelial cell line to release proinflammatory mediators causingmigration of macrophages, rapid recruitment of inflammatory cells to sitesof particle deposition, and the subsequent removal of the particles by phago-cytic cells (eg, macrophages and neutrophils). These observations are sug-gestive that certain classes of nanoparticles could be responsible fordestructive inflammatory processes in the lungs.

Environmental concernsAnother serious concern is the transformation of properties that engi-

neered nanomaterials undergo and how this may affect their interactionwith biologic systems. For example, pure carbon is used as graphite in pencillead, but arranged differently this carbon becomes a diamond. Fullerenesand nanotubes, which exemplify other carbon permutations, are attractivecandidates for many applications, including high-performance computing,photovoltaics, and drug delivery; however, these properties and dimensionsalso may make them dangerous when introduced into the environment.Moreover, different manufacturing methods can produce widely varyingproducts with different amounts of impurities. These differences may explainwhy fullerenes behave in some contexts as antioxidants and in others aspowerful oxidants, capable of working their way into the brain and damag-ing cell membranes.

Regulatory challengesIf regulations were to be based only on the research indicating potentially

dangerous properties, consumers might never see the health benefits of somefullerenes. Alternatively, if the wrong type of fullerenes were used as antiox-idants, the adverse consequences could be devastating, lending urgency tolearning what environmental and health effects these novel materials mayhave. A vast number of industries could be affected; however, at thistime, the necessary resources to oversee nanotoxicology studies are simplynot available.

The US Environmental Protection Agency (EPA) has just released a draftwhite paper on nanotechnology that considers the gaps in our knowledge ofits environmental and health effects. Box 3 summarizes its provisional rec-ommendations, which are staggering in terms of the resources that will berequired to meet the demands of this program. The sheer breadth of theseconcerns suggests that regulating nanotechnology may be a task far beyondthe capacity of a single government program. The EPA has not settled onhow it will regulate nanoengineered materials, but the substances probablywill come under the purview of environmental laws already on the booksand draw on the agency’s existing funding.

If the EPA fails to satisfactorily regulate nano-enabled products that turnout to be unsafe, the consequences could be catastrophic. Not only could

834 MORROW et al

Box 3. Summary of recommendations

Summary of workgroup recommendations regardingnanomaterials

6.1 Pollution prevention, stewardship and sustainabilityEPA should engage resources and expertise as nanotechnology

industries form and develop to encourage, develop, andsupport nanomaterial pollution prevention at its source andan approach of stewardship. Detailed pollution preventionrecommendations are identified in the text. Additionally theagency should draw on the next-generationnanotechnologies for applications that support environmentalstewardship and sustainability, such as green energy andgreen manufacturing.

6.2 ResearchEPA should undertake, collaborate on, and catalyze research on

various types of nanomaterials to better understand and applyinformation regarding theirChemical identification and characterizationEnvironmental fateEnvironmental detection and analysisPotential release and human exposuresHuman health effects assessmentEnvironmental technology applications

Specific research recommendations for each area are identifiedin the text.

6.3 Risk assessmentEPA should conduct case studies based on publicly available

information on several intentionally produced nanomaterials.Such case studies would be useful in further identifying uniqueconsiderations that should be focused on conducting riskassessments for the various types of nanomaterials. The casestudies also would aid in further identifying information gapsthat can be used to map areas of research that are relateddirectly with the risk-assessment process.

6.4 CollaborationEPA should continue and expand in collaborations regarding

nanomaterials applications and potential human andenvironmental health implications.

835RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

billions of dollars in R&D and profits be wasted, but nanotechnology-basedproducts would be lost, including those that could provide health and envi-ronmental benefits, such as reducing the side effects of cancer treatments orcleaning up toxic waste sites quickly.

In addition to greater funding and coordination of the efforts of multipleagencies, international cooperation will be required. As regulations are im-posed they will impinge most heavily upon small nanotechnology start-ups.This will drive innovative start-ups to build partnerships with other, largercompanies to meet regulatory requirements. In the final analysis, a govern-ment or an industry-sponsored fund to help such companies meet regulatoryguidelines may be essential for their products to make a profit.

Bullis [114] believes that aggressive action needs to be taken on environ-mental concerns to deliver the benefits that nanotechnology promises; how-ever, this will require an immediate, massive, and sustained effort.

Summary

Nanomedicine is a global business enterprise impacting universities, start-ups, and boardrooms of multinational corporations alike. Industry andgovernments clearly are beginning to envision nanomedicine’s enormouspotential. As long as government expenditure encourages facile technologytransfer to the private sector, nanotechnology eventually will blossom asa source for corporate investment and revenue. However, for nanomedicine(and nanotechnology) to truly become a global megatrend, the hype must beseparated from reality. In addition, societal, environmental, and ethical con-cerns will need to be addressed as scientific advances occur.

A clear definition of nanotechnology also is an issue that requires urgentattention. This problem exists because nanotechnology represents a clusterof technologies, each of which may have different characteristics and

6.5. Cross-Agency workgroupEPA should convene a standing cross-Agency group to foster

information sharing regarding risk assessment on regulatoryactivities for nanomaterials across program offices andregions.

6.6 TrainingEPA should continue and expand its activities aimed at training

Agency scientists and managers regarding potentialenvironmental applications and environmental implications ofnanotechnology.

Adapted from Nanotechnology Workgroup. Nanotechnology white paper. U.S.Environmental Protection Agency. Washington DC, 2007.

836 MORROW et al

applications. Government agencies, such as the FDA and PTO, use a rigiddefinition based on a scale of less than 100 nmda definition originally pro-posed by NNI; however, this definition clearly presents problems for under-standing nanopatent statistics and for the proper assessment of the scientific,legal, environmental, regulatory, and ethical implications of nanotechnol-ogy [19].

Although numerous novel nanomedicine-related applications are underdevelopment or nearing commercialization, the process of converting basicresearch in nanomedicine into commercially viable products will be long anddifficult. Realization of the full potential of nanomedicine may be years ordecades away, however recent advances in nanotechnology-related drug de-livery, diagnosis, and drug development are beginning to change the land-scape of medicine. Site-specific targeted drug delivery (made possible bythe availability of unique delivery platforms, such as dendrimers, nanopar-ticles, and nanoliposomes) and personalized medicine (a result of advancesin pharmacogenetics and pharmacogenomics) are just a few concepts on thehorizon.

Numerous bottlenecks may hinder commercialization. The confusion anddelays in patent examination at the PTO that are due to the burgeoningnumber of patent applications filed and the regulatory issues at the FDAwith respect to safety guidelines regarding nanotechnology are likely toimpede commercialization of nanomedicine products.

Nanoshadow on society

Nanotechnology has been promoted enthusiastically since its early days,and current prognostications for the future are full of optimistic predictions[115]. Without a doubt, the potential impact of nanomedicine on society willbe profound. Nanotechnology promises to transform our industrial baseand to have a dramatic impact on health care and our long-term qualityof life. Although nanodevices, such as nanobots capable of performing in-ternal therapeutic functions in vivo, are still in the realm of science fiction,incremental technologic advances across multiple scientific disciplines willcontinue to be proposed, validated, patented, and commercialized.Advances in delivering nanotherapies, miniaturization of analytic tools,improved computational and memory capabilities, and developmentsin remote communications will be forthcoming. The unfolding path ofnanoadvances will cross new frontiers to the understanding and practiceof medicine [22]. The ultimate goal is comprehensive monitoring, repair,and improvement of all human biologic systems.

The question that the authors wish to address in these concluding para-graphs is not whether nanotechnology will greatly influence medicine; this isa given. Rather, will nanotechnology be a truly disruptive technology thatwill change the course of civilization? Despite a proliferation of gadgetry,the scientific advances that we have seen in the last 50 years in the fields of

837RECENT ADVANCES IN BASIC AND CLINICAL NANOMEDICINE

medicine, communications, transportation, and manufacturing are mainlyincremental, and some not even that. For instance, air travel has not changedsignificantly since the 1960s, nor has building construction, automobilemanufacturing, food preparation, entertainment, or leisure time activities.

Clearly, nanomedicine holds great promise at this incremental level, giventhe many applications in drug delivery, diagnostics, detection, discovery,sensing, and imaging. Life science operations will continue to benefit fromthe ongoing research in nanopharmaceuticals because they have the abilityto enhance the delivery and effectiveness of traditional drugs while revolu-tionizing and accelerating future drug discovery and developmentdimprov-ing productivity and providing new drug delivery techniques.

Risks of nanomedicine

Goldstein [116] states that by 2016, ‘‘.your doctor will be capable ofscanning your entire genome within a few minutes.’’ The article elaborateson the many ethical dilemmas posed by knowledge of risk factors that areknown only in probabilistic terms and the question of how individualswill be able to afford vastly expensive new medical procedures predicatedon nanomedicine’s diagnostic and therapeutic potentials.

But, as Yogi Berra said, ‘‘It’s difficult to make predictions, especiallyabout the future.’’ The authors must caution that unlike the inexorablegrinding of Moore’s Law (the notion that everything good about computersdoubles every 18 months), the therapies and diagnostics of nanomedicinecannot move into the market place without extensive clinical evaluation,and this process runs to years (again, consider the rise of antibody therapeu-tics). The authors submit that this long lag time will provide breathing roomfor society to sort out the complex social and political issues flowing fromthe potentially ‘‘disruptive’’ features of this technology.

In addition, there is great concern over the environmental and healthrisks of nanotechnology. There have been dire warnings over the dangersinherent in this technology. Regulatory agencies are still attempting to for-mulate an appropriate set of guidelines regarding exposure to nanomaterialsand naoparticles, a difficult task given the current level of uncertainly.The authors argue that time to consolidate these discoveries is essential.The history of science is replete with technological innovations that movedfrom the laboratory into commercialization, only to precipitate grievousconsequences once they were disseminated widely. Pesticides, atmosphericCO2, atmospheric fluorocarbons, radioisotopes, thalidomide: the list goeson and on. Today, the stakes are much higher. Repercussions (real andimagined) may be rapidly forthcoming, and blame will be assigned throughthe courts, which many would argue is not the most effective route to thetruth.

Goldstein [116] warns that the volume of data pouring out of the nano-technology diagnostic spigot eventually may overwhelm the ability of

838 MORROW et al

regulatory systems and agencies to evaluate it, making effective treatmentimpossible. This situation could arise if the amount of clinical informationgenerated was vast and no method of triaging it existed. This would forcephysicians to wade through haystacks of irrelevancies in search of a few pre-cious needles of clinical wisdom.

Yet today, although physicians are often overwhelmed by clinical data,the vast amount of which is only of marginal significance, they nonethelessusually make accurate diagnoses, setting aside unsupportive data. Clearly,incisive diagnostics could eliminate fruitless treatment and save the systemvast amounts of resources.

Goldstein also discusses a world in which only the rich will have access totreatment, and the poor are denied even knowledge of their diseases; how-ever, this is precisely what our health care system faces today. Althoughthe United States allocates 23% of gross domestic product for healthcare, it ranks twenty-third for lowest rate of infant mortality and seven-teenth for longevity among countries listed [117]. Thus, despite the factthat our health care system spends far more per capita than any other coun-try in the world, the most relevant statistics place us far below many otherindustrialized countries. The authors conclude that Goldstein’s dire predic-tions concerning the negative effects of nanomedicine seem to have alreadybeen realized in the absence of any nanomedicine products in the clinic.

The promise of nanomedicine

It appears to the authors that the failure of the health care establishment tomeet the needs of the American people is the result of mismanagement, poorplanning, and greed. Given the political gridlock and the failure of our polit-ical system to institute meaningful health care reform, the authors submitthat new (nano)technologies may offer the only hope for systematic, afford-able, and long-term improvements to the health status of our population.This is because nanotherapies (combined with related advances in surgery,therapeutics, diagnostics, and computerization) coulddin the long rundbemuch more economical, effective, and safe and could greatly reduce thecost of or substantially eliminate current medical procedures. For example,compare stents with bypass operations or antibody therapy for Crohn’s dis-ease versus surgery. The next few years will reveal whether the concepts pre-sented in this article are incremental (eg, lowering cholesterol levels) orrevolutionary (eg, ending cardiovascular disease).

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